title: Thrombospondin-1 induction in the diabetic myocardium stabilizes the cardiac matrix in addition to promoting vascular rarefaction through angiopoietin-2 upregulation.
abstract: BACKGROUND
  Diabetes mellitus is associated with cardiac fibrosis. Matricellular proteins are induced in fibrotic conditions and modulate fibrogenic and angiogenic responses by regulating growth factor signaling.
  
  
  OBJECTIVE
  Our aim was to test the hypothesis that the prototypical matricellular protein thrombospondin (TSP)-1, a potent angiostatic molecule and crucial activator of transforming growth factor-β, may play a key role in remodeling of the diabetic heart.
  
  
  RESULTS
  Obese diabetic db/db mice exhibited marked myocardial TSP-1 upregulation in the interstitial and perivascular space. To study the role of TSP-1 in remodeling of the diabetic heart, we generated and characterized db/db TSP-1(-/-) (dbTSP) mice. TSP-1 disruption did not significantly affect weight gain and metabolic function in db/db animals. When compared with db/db animals, dbTSP mice had increased left ventricular dilation associated with mild nonprogressive systolic dysfunction. Chamber dilation in dbTSP mice was associated with decreased myocardial collagen content and accentuated matrix metalloproteinase-2 and -9 activity. TSP-1 disruption did not affect inflammatory gene expression and activation of transforming growth factor-β/small mothers against decapendaplegic signaling in the db/db myocardium. In cardiac fibroblasts populating collagen pads, TSP-1 incorporation into the matrix did not activate transforming growth factor-β responses, but inhibited leptin-induced matrix metalloproteinase-2 activation. TSP-1 disruption abrogated age-associated capillary rarefaction in db/db mice, attenuating myocardial upregulation of angiopoietin-2, a mediator that induces vascular regression. In vitro, TSP-1 stimulation increased macrophage, but not endothelial cell, angiopoietin-2 synthesis.
  
  
  CONCLUSIONS
  TSP-1 upregulation in the diabetic heart prevents chamber dilation by exerting matrix-preserving actions on cardiac fibroblasts and mediates capillary rarefaction through effects that may involve angiopoietin-2 upregulation.
authors.affiliation: From the Department of Medicine (Cardiology), Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY (C.G.-Q., M.C., A.B., P.K., D.-W.L., A.S., O.F., M.D., A.S., N.G.F.); and Department of Medicine, Baylor College of Medicine, Houston, TX (C.G.-Q., A.B., M.D., N.G.F.).
authors.forename: Carlos
authors.initials: C
authors.lastname: Gonzalez-Quesada
authors.forename: Michele
authors.initials: M
authors.lastname: Cavalera
authors.forename: Anna
authors.initials: A
authors.lastname: Biernacka
authors.forename: Ping
authors.initials: P
authors.lastname: Kong
authors.forename: Dong-Wook
authors.initials: DW
authors.lastname: Lee
authors.forename: Amit
authors.initials: A
authors.lastname: Saxena
authors.forename: Olga
authors.initials: O
authors.lastname: Frunza
authors.forename: Marcin
authors.initials: M
authors.lastname: Dobaczewski
authors.forename: Arti
authors.initials: A
authors.lastname: Shinde
authors.forename: Nikolaos G
authors.initials: NG
authors.lastname: Frangogiannis
mesh_terms: D042702:Angiopoietin-2 / Q000096:biosynthesis*; D000818:Animals; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D009206:Myocardium / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D019700:Thrombospondin 1 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology*; D020257:Ventricular Remodeling / Q000235:genetics*
chemical_list: D042702:Angiopoietin-2; D019700:Thrombospondin 1; C585483:Thbs1 protein, mouse
keywords: diabetic cardiomyopathies; fibrosis; matrix metalloproteinases; thrombospondins; ventricular remodeling